1 610 130 BEYOND THE GENOME: EPIGENETIC MECHANISMS IN LUNG REMODELING. THE LUNG DEVELOPS FROM A VERY SIMPLE OUTPOUCHING OF THE FOREGUT INTO A HIGHLY COMPLEX, FINELY STRUCTURED ORGAN WITH MULTIPLE SPECIALIZED CELL TYPES THAT ARE REQUIRED FOR ITS NORMAL PHYSIOLOGICAL FUNCTION. DURING BOTH THE DEVELOPMENT OF THE LUNG AND ITS REMODELING IN THE CONTEXT OF DISEASE OR RESPONSE TO INJURY, GENE EXPRESSION MUST BE ACTIVATED AND SILENCED IN A COORDINATED MANNER TO ACHIEVE THE TREMENDOUS PHENOTYPIC HETEROGENEITY OF CELL TYPES REQUIRED FOR HOMEOSTASIS AND PATHOGENESIS. EPIGENETIC MECHANISMS, CONSISTING OF DNA BASE MODIFICATIONS SUCH AS METHYLATION, ALTERATION OF HISTONES RESULTING IN CHROMATIN MODIFICATION, AND THE ACTION OF NONCODING RNA, CONTROL THE REGULATION OF INFORMATION "BEYOND THE GENOME" REQUIRED FOR BOTH LUNG MODELING AND REMODELING. EPIGENETIC REGULATION IS SUBJECT TO MODIFICATION BY ENVIRONMENTAL STIMULI, SUCH AS OXIDATIVE STRESS, INFECTION, AND AGING, AND IS THUS CRITICALLY IMPORTANT IN CHRONIC REMODELING DISORDERS SUCH AS IDIOPATHIC PULMONARY FIBROSIS (IPF), CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BRONCHOPULMONARY DYSPLASIA (BPD), AND PULMONARY HYPERTENSION (PH). TECHNOLOGICAL ADVANCES HAVE MADE IT POSSIBLE TO EVALUATE GENOME-WIDE EPIGENETIC CHANGES (EPIGENOMICS) IN DISEASES OF LUNG REMODELING, CLARIFYING EXISTING PATHOPHYSIOLOGICAL PARADIGMS AND UNCOVERING NOVEL MECHANISMS OF DISEASE. MANY OF THESE REPRESENT NEW THERAPEUTIC TARGETS. ADVANCES IN EPIGENOMIC TECHNOLOGY WILL ACCELERATE OUR UNDERSTANDING OF LUNG DEVELOPMENT AND REMODELING, AND LEAD TO NOVEL TREATMENTS FOR CHRONIC LUNG DISEASES. 2014 2 3966 38 LONG NONCODING TRANSCRIPTOME IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC AIRWAY INFLAMMATION FROM RECURRING EXPOSURES TO NOXIOUS ENVIRONMENTAL STIMULI RESULTS IN A PROGRESSIVE AND IRREVERSIBLE AIRFLOW LIMITATION AND THE LUNG PARENCHYMAL DAMAGE THAT CHARACTERIZES CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE LARGE VARIABILITY OBSERVED IN THE ONSET AND PROGRESSION OF COPD IS PRIMARILY DRIVEN BY COMPLEX GENE-ENVIRONMENT INTERACTIONS. THE TRANSCRIPTOMIC AND EPIGENETIC MEMORY POTENTIAL OF LUNG EPITHELIAL AND INNATE IMMUNE CELLS DRIVE RESPONSES, SUCH AS MUCUS HYPERREACTIVITY AND AIRWAY REMODELING, THAT ARE TIGHTLY REGULATED BY VARIOUS MOLECULAR MECHANISMS, FOR WHICH SEVERAL CANDIDATE SUSCEPTIBILITY GENES HAVE BEEN DESCRIBED. HOWEVER, THE RECENTLY DESCRIBED NONCODING RNA SPECIES, IN PARTICULAR THE LONG NONCODING RNAS, MAY ALSO HAVE AN IMPORTANT ROLE IN MODULATING PULMONARY RESPONSES TO CHRONIC INHALATION OF TOXIC SUBSTANCES AND THE DEVELOPMENT OF COPD. THIS REVIEW OUTLINES THE FEATURES OF LONG NONCODING RNAS THAT HAVE BEEN IMPLICATED IN REGULATING THE AIRWAY INFLAMMATORY RESPONSES TO CIGARETTE SMOKE EXPOSURE AND THEIR POSSIBLE ASSOCIATION WITH COPD PATHOGENESIS. AS COPD CONTINUES TO DEBILITATE THE INCREASINGLY AGING POPULATION AND CONTRIBUTE TO HIGHER MORBIDITY AND MORTALITY RATES WORLDWIDE, THE SEARCH FOR BETTER BIOMARKERS AND ALTERNATIVE THERAPEUTIC OPTIONS IS PIVOTAL. 2019 3 4445 35 MOLECULAR LINKS BETWEEN COPD AND LUNG CANCER: NEW TARGETS FOR DRUG DISCOVERY? COPD AND LUNG CANCER ARE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE, AND THEY SHARE A COMMON ENVIRONMENTAL RISK FACTOR IN CIGARETTE SMOKE EXPOSURE AND A GENETIC PREDISPOSITION REPRESENTED BY THEIR INCIDENCE IN ONLY A FRACTION OF SMOKERS. THIS REFLECTS THE ABILITY OF CIGARETTE SMOKE TO INDUCE AN INFLAMMATORY RESPONSE IN THE AIRWAYS OF SUSCEPTIBLE SMOKERS. MOREOVER, COPD COULD BE A DRIVING FACTOR IN LUNG CANCER, BY INCREASING OXIDATIVE STRESS AND THE RESULTING DNA DAMAGE AND REPRESSION OF THE DNA REPAIR MECHANISMS, CHRONIC EXPOSURE TO PRO-INFLAMMATORY CYTOKINES, REPRESSION OF INNATE IMMUNITY AND INCREASED CELLULAR PROLIFERATION. AREAS COVERED: WE HAVE FOCUSED OUR REVIEW ON THE POTENTIAL PATHOGENIC MOLECULAR LINKS BETWEEN TOBACCO SMOKING-RELATED COPD AND LUNG CANCER AND THE POTENTIAL MOLECULAR TARGETS FOR NEW DRUG DEVELOPMENT BY UNDERSTANDING THE COMMON SIGNALING PATHWAYS INVOLVED IN COPD AND LUNG CANCER. EXPERT COMMENTARY: RESEARCH IN THIS FIELD IS MOSTLY LIMITED TO ANIMAL MODELS OR SMALL CLINICAL TRIALS. LARGE CLINICAL TRIALS ARE NEEDED BUT MOSTLY COMBINED MODELS OF COPD AND LUNG CANCER ARE NECESSARY TO INVESTIGATE THE PROCESSES CAUSED BY CHRONIC INFLAMMATION, INCLUDING GENETIC AND EPIGENETIC ALTERATION, AND THE EXPRESSION OF INFLAMMATORY MEDIATORS THAT LINK COPD AND LUNG CANCER, TO IDENTIFY NEW MOLECULAR THERAPEUTIC TARGETS. 2019 4 2357 43 EPIGENETIC REGULATION OF PULMONARY INFLAMMATION. PULMONARY DISEASE SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), ASTHMA, PULMONARY FIBROSIS AND PULMONARY HYPERTENSION ARE THE LEADING CAUSE OF DEATHS. MORE IMPORTANTLY, LUNG DISEASES ARE ON THE RISE AND ENVIRONMENTAL FACTORS INDUCED EPIGENETIC MODIFICATIONS ARE MAJOR PLAYERS ON THIS INCREASED PREVALENCE. IT HAS BEEN REPORTED THAT DYSREGULATION OF GENES INVOLVED IN EPIGENETIC REGULATION SUCH AS THE HISTONE DEACETYLASE (HDACS) AND HISTONE ACETYLTRANSFERASE (HATS) PLAY IMPORTANT ROLE IN LUNG HEALTH AND PULMONARY DISEASE PATHOGENESIS. INFLAMMATION IS AN ESSENTIAL COMPONENT OF RESPIRATORY DISEASES. INJURY AND INFLAMMATION TRIGGER RELEASE OF EXTRACELLULAR VESICLES THAT CAN ACT AS EPIGENETIC MODIFIERS THROUGH TRANSFER OF EPIGENETIC REGULATORS SUCH AS MICRORNAS (MIRNAS), LONG NON-CODING RNAS (LNCRNAS), PROTEINS AND LIPIDS, FROM ONE CELL TO ANOTHER. THE IMMUNE DYSREGULATIONS CAUSED BY THE CARGO CONTENTS ARE IMPORTANT CONTRIBUTORS OF RESPIRATORY DISEASE PATHOGENESIS. N6 METHYLATION OF RNA IS ALSO EMERGING TO BE A CRITICAL MECHANISM OF EPIGENETIC ALTERATION AND UPREGULATION OF IMMUNE RESPONSES TO ENVIRONMENTAL STRESSORS. EPIGENETIC CHANGES SUCH AS DNA METHYLATION ARE STABLE AND OFTEN LONG TERM AND CAUSE ONSET OF CHRONIC LUNG CONDITIONS. THESE EPIGENETIC PATHWAYS ARE ALSO BEING UTILIZED FOR THERAPEUTIC INTERVENTION IN SEVERAL LUNG CONDITIONS. 2023 5 1597 43 DNA METHYLATION REGULATED GENE EXPRESSION IN ORGAN FIBROSIS. DNA METHYLATION IS A MAJOR EPIGENETIC MECHANISM TO REGULATE GENE EXPRESSION. EPIGENETIC REGULATION, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND RNA INTERFERENCE, RESULTS IN HERITABLE CHANGES IN GENE EXPRESSION INDEPENDENT OF ALTERATIONS IN DNA SEQUENCE. EPIGENETIC REGULATION OFTEN OCCURS IN RESPONSE TO AGING AND ENVIRONMENT STIMULI, INCLUDING EXPOSURES AND DIET. STUDIES HAVE SHOWN THAT DNA METHYLATION IS CRITICAL IN THE PATHOGENESIS OF FIBROSIS INVOLVING MULTIPLE ORGAN SYSTEMS, CONTRIBUTING TO SIGNIFICANT MORBIDITY AND MORTALITY. ABERRANT DNA METHYLATION CAN SILENCE OR ACTIVATE GENE EXPRESSION PATTERNS THAT DRIVE THE FIBROSIS PROCESS. FIBROSIS IS A PATHOLOGICAL WOUND HEALING PROCESS IN RESPONSE TO CHRONIC INJURY. IT IS CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX PRODUCTION AND ACCUMULATION, WHICH EVENTUALLY AFFECTS ORGAN ARCHITECTURE AND RESULTS IN ORGAN FAILURE. FIBROSIS CAN AFFECT A WIDE RANGE OF ORGANS, INCLUDING THE HEART AND LUNGS, AND HAVE LIMITED THERAPEUTIC OPTIONS. DNA METHYLATION, LIKE OTHER EPIGENETIC PROCESS, IS REVERSIBLE, THEREFORE REGARDED AS ATTRACTIVE THERAPEUTIC INTERVENTIONS. ALTHOUGH EPIGENETIC MECHANISMS ARE HIGHLY INTERACTIVE AND OFTEN REINFORCING, THIS REVIEW DISCUSSES DNA METHYLATION-DEPENDENT MECHANISMS IN THE PATHOGENESIS OF ORGAN FIBROSIS, WITH FOCUS ON CARDIAC AND PULMONARY FIBROSIS. WE DISCUSS SPECIFIC PRO- AND ANTI-FIBROTIC GENES AND PATHWAYS REGULATED BY DNA METHYLATION IN ORGAN FIBROSIS; WE FURTHER HIGHLIGHT THE POTENTIAL BENEFITS AND SIDE-EFFECTS OF EPIGENETIC THERAPIES IN FIBROTIC DISORDERS. 2017 6 4026 32 LUNG CANCER AND ITS ASSOCIATION WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: UPDATE ON NEXUS OF EPIGENETICS. PURPOSE OF REVIEW: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER ARE THE LEADING CAUSES OF MORBIDITY AND MORTALITY WORLDWIDE. THE CURRENT RESEARCH IS FOCUSED ON IDENTIFYING THE COMMON AND DISPARATE EVENTS INVOLVED IN EPIGENETIC MODIFICATIONS THAT CONCURRENTLY OCCUR DURING THE PATHOGENESIS OF COPD AND LUNG CANCER. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE THE CURRENT KNOWLEDGE AND UNDERSTANDING OF EPIGENETIC MODIFICATIONS IN PATHOGENESIS OF COPD AND LUNG CANCER. RECENT FINDINGS: THIS REVIEW PROVIDES AN UPDATE ON ADVANCES OF HOW EPIGENETIC MODIFICATIONS ARE LINKED TO COPD AND LUNG CANCER, AND THEIR COMMONALITIES AND DISPARITIES. THE KEY EPIGENETIC MODIFICATION ENZYMES (E.G. DNA METHYLTRANSFERASES -- CPG METHYLATION, HISTONE ACETYLASES/DEACETYLASES AND HISTONE METHYLTRANSFERASES/DEMETHYLASES) THAT ARE IDENTIFIED TO PLAY AN IMPORTANT ROLE IN COPD AND LUNG TUMORIGENESIS AND PROGRESSION ARE DESCRIBED IN THIS REVIEW. SUMMARY: DISTINCT DNA METHYLTRANSFERASES AND HISTONE MODIFICATION ENZYMES ARE DIFFERENTIALLY INVOLVED IN PATHOGENESIS OF LUNG CANCER AND COPD, ALTHOUGH SOME OF THE MODIFICATIONS ARE COMMON. UNDERSTANDING THE EPIGENETIC MODIFICATIONS INVOLVED IN PATHOGENESIS OF LUNG CANCER OR COPD WITH RESPECT TO COMMON AND DISPARATE MECHANISMS WILL LEAD TO TARGETING OF EPIGENETIC THERAPIES AGAINST THESE DISORDERS. 2011 7 2161 37 EPIGENETIC MECHANISMS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. EPIGENETIC MODIFICATION MAY AFFECT THE EXPRESSION OF MULTIPLE INFLAMMATORY GENES IN LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). MAJOR EPIGENETIC EVENTS INCLUDE DNA METHYLATION AND VARIOUS POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, SUCH AS HISTONE METHYLATION, ACETYLATION, PHOSPHORYLATION, UBIQUITINATION, AND SUMOYLATION. ENZYMES WHICH REGULATE THESE EPIGENETIC MODIFICATIONS CAN BE ACTIVATED BY SMOKING. BOTH ENVIRONMENTAL AND GENETIC FACTORS PLAY SIGNIFICANT EFFECT IN DEVELOPMENT OF COPD WHICH HAVE BEEN REPORTED BY MOST REFERENCES; HOWEVER, LITTLE IS KNOWN ABOUT THE EPIGENETIC PATHWAYS INVOLVED IN THE DISEASE. UNDERSTANDING THE EPIGENETIC MECHANISMS CAN HELP US CLARIFY THE PATHOGENESIS OF COPD AND IDENTIFY NOVEL TARGETS FOR DEVELOPING NEW THERAPIES FOR PATIENTS WITH COPD. 2015 8 2527 26 EPIGENETICS APPROACHES TOWARD PRECISION MEDICINE FOR IDIOPATHIC PULMONARY FIBROSIS: FOCUS ON DNA METHYLATION. GENETIC INFORMATION IS NOT TRANSMITTED SOLELY BY DNA BUT BY THE EPIGENETICS PROCESS. EPIGENETICS DESCRIBES MOLECULAR MISSING LINK PATHWAYS THAT COULD BRIDGE THE GAP BETWEEN THE GENETIC BACKGROUND AND ENVIRONMENTAL RISK FACTORS THAT CONTRIBUTE TO THE PATHOGENESIS OF PULMONARY FIBROSIS. SPECIFIC EPIGENETIC PATTERNS, ESPECIALLY DNA METHYLATION, HISTONE MODIFICATIONS, LONG NON-CODING, AND MICRORNA (MIRNAS), AFFECT THE ENDOPHENOTYPES UNDERLYING THE DEVELOPMENT OF IDIOPATHIC PULMONARY FIBROSIS (IPF). AMONG ALL THE EPIGENETIC MARKS, DNA METHYLATION MODIFICATIONS HAVE BEEN THE MOST WIDELY STUDIED IN IPF. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE CONCERNING DNA METHYLATION CHANGES IN PULMONARY FIBROSIS AND DEMONSTRATES A PROMISING NOVEL EPIGENETICS-BASED PRECISION MEDICINE. 2023 9 970 29 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER: COMMON PATHWAYS FOR PATHOGENESIS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER COMPRISE THE LEADING CAUSES OF LUNG DISEASE-RELATED MORTALITY WORLDWIDE. EXPOSURE TO TOBACCO SMOKE IS A MUTUAL AETIOLOGY UNDERLYING THE TWO DISEASES, ACCOUNTING FOR ALMOST 90% OF CASES. THERE IS ACCUMULATING EVIDENCE SUPPORTING THE ROLE OF IMMUNE DYSFUNCTION, THE LUNG MICROBIOME, EXTRACELLULAR VESICLES AND UNDERLYING GENETIC SUSCEPTIBILITY IN THE DEVELOPMENT OF COPD AND LUNG CANCER. FURTHER, EPIGENETIC FACTORS, INVOLVING DNA METHYLATION AND MICRORNA EXPRESSION, HAVE BEEN IMPLICATED IN BOTH DISEASES. CHRONIC INFLAMMATION IS A KEY FEATURE OF COPD AND COULD BE A POTENTIAL DRIVER OF LUNG CANCER DEVELOPMENT. USING NEXT GENERATION TECHNOLOGIES, FURTHER STUDIES INVESTIGATING THE GENOMICS, EPIGENETICS AND GENE-ENVIRONMENT INTERACTION IN KEY MOLECULAR PATHWAYS WILL CONTINUE TO ELUCIDATE THE PATHOGENIC MECHANISMS UNDERLYING THE DEVELOPMENT OF COPD AND LUNG CANCER, AND CONTRIBUTE TO THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND PROGNOSTIC TOOLS FOR EARLY INTERVENTION AND PERSONALISED THERAPEUTIC STRATEGIES. 2019 10 5456 41 RESEARCH ADVANCES ON DNA METHYLATION IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC COMPLEX LUNG DISEASE WITH NO SPECIFIC TREATMENT AND POOR PROGNOSIS, CHARACTERIZED BY THE PULMONARY PROGRESSIVE FIBROSIS AND DYSFUNCTIONS THAT LEAD TO RESPIRATORY FAILURE. SEVERAL FACTORS MAY IMPACT THE PROGRESS OF IPF, INCLUDING AGE, CIGARETTE SMOKING, AND DUSTS, OF WHICH GENETIC AND EPIGENETIC FACTORS MAINLY CONTRIBUTE TO LUNG TISSUE FIBROSIS. DNA METHYLATION IS ONE OF EPIGENETIC PROCESSES THAT OCCUR IN MANY DISEASES AND REGULATE CHROMOSOMAL AND EXTRACHROMOSOMAL DNA FUNCTIONS IN RESPONSE TO ENVIRONMENTAL EXPOSURES. THE METHYLATION PLAYS PIVOTAL ROLES IN REGULATION OF GENE EXPRESSION TO FACILITATE THE FORMATION OF FIBROBLASTIC FOCI AND LUNG FIBROSIS. THIS CHAPTER WILL DESCRIBE ALTERATIONS AND EFFECTS OF THE DNA METHYLATION ON GENE EXPRESSION, THE POTENTIAL APPLICATION OF DNA METHYLATION AS A BIOMARKER, AND SIGNIFICANCE AS THERAPEUTIC TARGETS. THOSE UNDERSTANDING WILL PROVIDE US NEW INSIGHT INTO THE TREATMENT AND PROGNOSIS OF IPF. 2020 11 2455 48 EPIGENETIC TARGETS FOR NOVEL THERAPIES OF LUNG DISEASES. IN SPITE OF SUBSTANTIAL ADVANCES IN DEFINING THE IMMUNOBIOLOGY AND FUNCTION OF STRUCTURAL CELLS IN LUNG DISEASES THERE IS STILL INSUFFICIENT KNOWLEDGE TO DEVELOP FUNDAMENTALLY NEW CLASSES OF DRUGS TO TREAT MANY LUNG DISEASES. FOR EXAMPLE, THERE IS A COMPELLING NEED FOR NEW THERAPEUTIC APPROACHES TO ADDRESS SEVERE PERSISTENT ASTHMA THAT IS INSENSITIVE TO INHALED CORTICOSTEROIDS. ALTHOUGH THE PREVALENCE OF STEROID-RESISTANT ASTHMA IS 5-10%, SEVERE ASTHMATICS REQUIRE A DISPROPORTIONATE LEVEL OF HEALTH CARE SPENDING AND CONSTITUTE A MAJORITY OF FATAL ASTHMA EPISODES. NONE OF THE ESTABLISHED DRUG THERAPIES INCLUDING LONG-ACTING BETA AGONISTS OR INHALED CORTICOSTEROIDS REVERSE ESTABLISHED AIRWAY REMODELING. OBSTRUCTIVE AIRWAYS REMODELING IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), RESTRICTIVE REMODELING IN IDIOPATHIC PULMONARY FIBROSIS (IPF) AND OCCLUSIVE VASCULAR REMODELING IN PULMONARY HYPERTENSION ARE SIMILARLY UNRESPONSIVE TO CURRENT DRUG THERAPY. THEREFORE, DRUGS ARE NEEDED TO ACHIEVE LONG-ACTING SUPPRESSION AND REVERSAL OF PATHOLOGICAL AIRWAY AND VASCULAR REMODELING. NOVEL DRUG CLASSES ARE EMERGING FROM ADVANCES IN EPIGENETICS. NOVEL MECHANISMS ARE EMERGING BY WHICH CELLS ADAPT TO ENVIRONMENTAL CUES, WHICH INCLUDE CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND REGULATION OF TRANSCRIPTION AND TRANSLATION BY NONCODING RNAS. IN THIS REVIEW WE WILL SUMMARIZE CURRENT EPIGENETIC APPROACHES BEING APPLIED TO PRECLINICAL DRUG DEVELOPMENT ADDRESSING IMPORTANT THERAPEUTIC CHALLENGES IN LUNG DISEASES. THESE CHALLENGES ARE BEING ADDRESSED BY ADVANCES IN LUNG DELIVERY OF OLIGONUCLEOTIDES AND SMALL MOLECULES THAT MODIFY THE HISTONE CODE, DNA METHYLATION PATTERNS AND MIRNA FUNCTION. 2015 12 6199 38 THE IMPORTANCE OF EPIGENETICS IN THE DEVELOPMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE. IT IS GENERALLY ACCEPTED THAT GENETIC PREDISPOSITION PLAYS A ROLE IN COPD DEVELOPMENT IN SUSCEPTIBLE INDIVIDUALS. THEREFORE, MANY CANDIDATE GENES THAT COULD BE LINKED TO THE DEVELOPMENT OF DISEASE HAVE BEEN EXAMINED IN COPD. HOWEVER, INCONSISTENT RESULTS IN DIFFERENT STUDY POPULATIONS OFTEN LIMIT THIS APPROACH, SUGGESTING THAT NOT ONLY GENETICS, BUT ALSO OTHER FACTORS, MAY BE CONTRIBUTED TO THE SUSCEPTIBILITY TO COPD. EPIGENETIC MECHANISMS CAN AFFECT THE TRANSCRIPTIONAL ACTIVITY OF SPECIFIC GENES, AT DIFFERENT POINTS IN TIME, AND IN DIFFERENT ORGANS. MOREOVER, THESE MECHANISMS CAN HAVE AN EFFECT ON PEOPLE'S HEALTH. RECENTLY, THERE IS EMERGING EVIDENCE SUPPORTING A ROLE OF EPIGENETICS FOR THE REGULATION OF INFLAMMATORY GENES IN DISEASES SUCH AS ASTHMA AND COPD. MOREOVER, RECENT STUDIES SUGGEST THAT THE CURRENTLY USED TREATMENTS INCLUDING CORTICOSTEROIDS MAY WORK THROUGH EPIGENETIC MECHANISMS. EPIGENETIC REGULATION CAN BE REPROGRAMMED, POTENTIALLY AFFECTING THE RISK, AETIOLOGY AND TREATMENT OF VARIOUS DISEASE STATES. THE EPIGENETICALLY INFLUENCED PHENOTYPE COULD BE REVERSED WITH DEMETHYLATING OR DEACETYLATING AGENTS, CONSISTENT WITH EPIGENETIC PLASTICITY. THE POSTNATAL REVERSIBILITY OF THESE METHYLATION OR ACETYLATION EVENTS MAY THEREFORE PROVIDE GOOD OPPORTUNITIES FOR INTERVENTION. THE RECOGNITION OF THE ROLE OF GENETIC AND EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF COPD MAY IDENTIFY NOVEL TARGETS THAT HATCH NEW THERAPIES FOR PATIENTS WITH COPD. 2011 13 3100 43 GENOMIC IMPACT OF CIGARETTE SMOKE, WITH APPLICATION TO THREE SMOKING-RELATED DISEASES. THERE IS CONSIDERABLE EVIDENCE THAT INHALED TOXICANTS SUCH AS CIGARETTE SMOKE CAN CAUSE BOTH IRREVERSIBLE CHANGES TO THE GENETIC MATERIAL (DNA MUTATIONS) AND PUTATIVELY REVERSIBLE CHANGES TO THE EPIGENETIC LANDSCAPE (CHANGES IN THE DNA METHYLATION AND CHROMATIN MODIFICATION STATE). THE DISEASES THAT ARE BELIEVED TO INVOLVE GENETIC AND EPIGENETIC PERTURBATIONS INCLUDE LUNG CANCER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND CARDIOVASCULAR DISEASE (CVD), ALL OF WHICH ARE STRONGLY LINKED EPIDEMIOLOGICALLY TO CIGARETTE SMOKING. IN THIS REVIEW, WE HIGHLIGHT THE SIGNIFICANCE OF GENOMICS AND EPIGENOMICS IN THESE MAJOR SMOKING-RELATED DISEASES. WE ALSO SUMMARIZE THE IN VITRO AND IN VIVO FINDINGS ON THE SPECIFIC PERTURBATIONS THAT SMOKE AND ITS CONSTITUENT COMPOUNDS CAN INFLICT UPON THE GENOME, PARTICULARLY ON THE PULMONARY SYSTEM. FINALLY, WE REVIEW STATE-OF-THE-ART GENOMICS AND NEW TECHNIQUES SUCH AS HIGH-THROUGHPUT SEQUENCING AND GENOME-WIDE CHROMATIN ASSAYS, RAPIDLY EVOLVING TECHNIQUES WHICH HAVE ALLOWED EPIGENETIC CHANGES TO BE CHARACTERIZED AT THE GENOME LEVEL. THESE TECHNIQUES HAVE THE POTENTIAL TO SIGNIFICANTLY IMPROVE OUR UNDERSTANDING OF THE SPECIFIC MECHANISMS BY WHICH EXPOSURE TO ENVIRONMENTAL CHEMICALS CAUSES DISEASE. SUCH MECHANISTIC KNOWLEDGE PROVIDES A VARIETY OF OPPORTUNITIES FOR ENHANCED PRODUCT SAFETY ASSESSMENT AND THE DISCOVERY OF NOVEL THERAPEUTIC INTERVENTIONS. 2012 14 2457 41 EPIGENETIC TARGETS FOR THERAPEUTIC APPROACHES IN COPD AND ASTHMA. NUTRIGENOMICS - POSSIBLE OR ILLUSIVE. OXIDATIVE STRESS GENERATED BY CIGARETTE SMOKING, ENVIRONMENTAL POLLUTION, OR OTHER NOXIOUS PARTICLES LEADS TO EPIGENETIC CHANGES IN THE CELLS OF THE RESPIRATORY TRACT. THEY REFLECT CELL ADAPTATION IN RESPONSE TO CHRONIC EXPOSURE TO EXTERNAL FACTORS. ALTHOUGH THERE IS NO CHANGE IN THE GENETIC CODE, EPIGENETIC CHANGES MAY BE HERITABLE AND TRANSLATED FROM ONE GENERATION TO ANOTHER, ACCUMULATING ABNORMALITIES AND RENDERING CELLS INTO ENTIRELY DIFFERENT PHENOTYPE, CAUSING DISEASE. DNA METHYLATION, POST-TRANSLATION HISTONE MODIFICATION, UBIQUITINATION, SUMOYLATION AND MIRNA TRANSCRIPTIONAL REGULATION ARE THE MAJOR PROCESSES THAT ARE RESPONSIBLE FOR THE EPIGENETIC CONTROL OF GENE EXPRESSION. ALL OF THEM ARE REVERSIBLE. THEY CAN BE REGULATED BY TARGETING SPECIFIC ENZYMES/PROTEINS INVOLVED IN THE PROCESS IN ORDER TO MITIGATE INFLAMMATION. CHRONIC RESPIRATORY DISEASES HAVE EPIGENETIC SIGNATURES THAT AFFECT GENE EXPRESSION IN THE LUNG. TARGETING THEM PROVIDES THE DEVELOPMENT OF NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES IN RESPIRATORY MEDICINE. NUTRIGENOMICS REVEALS THE BENEFICIAL EFFECT OF NATURAL PHYTOCHEMICALS, AFFECTING KEY STEPS IN THE SIGNALING PATHWAYS OF CHRONIC RESPIRATORY DISEASES. 2019 15 4112 37 MECHANISMS CONTRIBUTING TO THE COMORBIDITY OF COPD AND LUNG CANCER. LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) OFTEN CO-OCCUR, AND INDIVIDUALS WITH COPD ARE AT A HIGHER RISK OF DEVELOPING LUNG CANCER. WHILE THE UNDERLYING MECHANISM FOR THIS RISK IS NOT WELL UNDERSTOOD, ITS MAJOR CONTRIBUTING FACTORS HAVE BEEN PROPOSED TO INCLUDE GENOMIC, IMMUNE, AND MICROENVIRONMENT DYSREGULATION. HERE, WE REVIEW THE EVIDENCE AND SIGNIFICANT STUDIES THAT EXPLORE THE MECHANISMS UNDERLYING THE HEIGHTENED LUNG CANCER RISK IN PEOPLE WITH COPD. GENETIC AND EPIGENETIC CHANGES, AS WELL AS THE ABERRANT EXPRESSION OF NON-CODING RNAS, PREDISPOSE THE LUNG EPITHELIUM TO CARCINOGENESIS BY ALTERING THE EXPRESSION OF CANCER- AND IMMUNE-RELATED GENES. OXIDATIVE STRESS GENERATED BY TOBACCO SMOKING PLAYS A ROLE IN REDUCING GENOMIC INTEGRITY, PROMOTING EPITHELIAL-MESENCHYMAL-TRANSITION, AND GENERATING A CHRONIC INFLAMMATORY ENVIRONMENT. THIS LEADS TO ABNORMAL IMMUNE RESPONSES THAT PROMOTE CANCER DEVELOPMENT, THOUGH NOT ALL SMOKERS DEVELOP LUNG CANCER. SEX DIFFERENCES IN THE METABOLISM OF TOBACCO SMOKE PREDISPOSE FEMALES TO DEVELOPING COPD AND ACCUMULATING DAMAGE FROM OXIDATIVE STRESS THAT POSES A RISK FOR THE DEVELOPMENT OF LUNG CANCER. DYSREGULATION OF THE LUNG MICROENVIRONMENT AND MICROBIOME CONTRIBUTES TO CHRONIC INFLAMMATION, WHICH IS OBSERVED IN COPD AND KNOWN TO FACILITATE CANCER INITIATION IN VARIOUS TUMOR TYPES. FURTHER, THERE IS A NEED TO BETTER CHARACTERIZE AND IDENTIFY THE PROPORTION OF INDIVIDUALS WITH COPD WHO ARE AT A HIGH RISK FOR DEVELOPING LUNG CANCER. WE EVALUATE POSSIBLE NOVEL AND INDIVIDUALIZED SCREENING STRATEGIES, INCLUDING BIOMARKERS IDENTIFIED IN GENETIC STUDIES AND EXHALED BREATH CONDENSATE ANALYSIS. WE ALSO DISCUSS THE USE OF CORTICOSTEROIDS AND STATINS AS CHEMOPREVENTIVE AGENTS TO PREVENT LUNG CANCER. IT IS CRUCIAL THAT WE OPTIMIZE THE CURRENT METHODS FOR THE EARLY DETECTION AND MANAGEMENT OF LUNG CANCER AND COPD IN ORDER TO IMPROVE THE HEALTH OUTCOMES FOR A LARGE AFFECTED POPULATION. 2023 16 2333 33 EPIGENETIC REGULATION OF INFLAMMATION: THE METABOLOMICS CONNECTION. EPIGENETIC FACTORS ARE CONSIDERED THE REGULATOR OF COMPLEX MACHINERY BEHIND INFLAMMATORY DISORDERS AND SIGNIFICANTLY CONTRIBUTED TO THE EXPRESSION OF INFLAMMATION-ASSOCIATED GENES. EPIGENETIC MODIFICATIONS MODULATE VARIATION IN THE EXPRESSION PATTERN OF TARGET GENES WITHOUT AFFECTING THE DNA SEQUENCE. THE CURRENT KNOWLEDGE OF EPIGENETIC RESEARCH FOCUSED ON THEIR ROLE IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES THAT CAUSES MORBIDITY AND MORTALITY WORLDWIDE. INFLAMMATORY DISEASES ARE CATEGORIZED AS ACUTE AND CHRONIC BASED ON THE DISEASE SEVERITY AND ARE REGULATED BY THE EXPRESSION PATTERN OF VARIOUS GENES. HENCE, UNDERSTANDING THE ROLE OF EPIGENETIC MODIFICATIONS DURING INFLAMMATION PROGRESSION WILL CONTRIBUTE TO THE DISEASE OUTCOMES AND THERAPEUTIC APPROACHES. THIS REVIEW ALSO FOCUSES ON THE METABOLOMICS APPROACH ASSOCIATED WITH THE STUDY OF INFLAMMATORY DISORDERS. INFLAMMATORY RESPONSES AND METABOLIC REGULATION ARE HIGHLY INTEGRATED AND VARIOUS ADVANCED TECHNIQUES ARE ADOPTED TO STUDY THE METABOLIC SIGNATURE MOLECULES. HERE WE DISCUSS SEVERAL METABOLOMICS APPROACHES USED TO LINK INFLAMMATORY DISORDERS AND EPIGENETIC CHANGES. WE PROPOSED THAT DECIPHERING THE MECHANISM BEHIND THE INFLAMMATION-METABOLISM LOOP MAY HAVE IMMENSE IMPORTANCE IN BIOMARKERS RESEARCH AND MAY ACT AS A PRINCIPAL COMPONENT IN DRUG DISCOVERY AS WELL AS THERAPEUTIC APPLICATIONS. 2022 17 1539 30 DNA METHYLATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A LUNG DISEASE AFFECTED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. THEREFORE, THE ROLE OF EPIGENETICS IN THE PATHOGENESIS OF COPD HAS ATTRACTED MUCH ATTENTION. AS ONE OF THE THREE EPIGENETIC MECHANISMS, DNA METHYLATION HAS BEEN EXTENSIVELY STUDIED IN COPD. THE PRESENT REVIEW AIMS AT OVERVIEWING THE EFFECT OF DNA METHYLATION ON ETIOLOGY, PATHOGENESIS, PATHOPHYSIOLOGICAL CHANGES, AND COMPLICATIONS OF COPD. THE CLARIFICATION OF ABERRANT METHYLATION OF TARGET GENES, WHICH PLAY IMPORTANT ROLES IN THE INITIATION AND PROGRESSION OF COPD, WILL PROVIDE NEW DISEASE-SPECIFIC BIOMARKER AND TARGETS FOR EARLY DIAGNOSIS AND THERAPY. 2020 18 6212 33 THE INTERPLAY OF THE GENETIC ARCHITECTURE, AGING, AND ENVIRONMENTAL FACTORS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC FIBROSING LUNG DISEASE OF INDETERMINATE ETIOLOGY AND LIMITED THERAPEUTIC OPTIONS. THE INITIATION, DEVELOPMENT, AND PROGRESSION OF IPF ARE INFLUENCED BY GENETIC PREDISPOSITION, AGING, AND HOST AND ENVIRONMENTAL FACTORS, BUT THE MAGNITUDE OF THE CONTRIBUTION OF EACH OF THEM AND THE SEQUENCE OF THE PATHOGENIC EVENTS ARE UNCERTAIN. CURRENT EVIDENCE INDICATES THAT ACCUMULATED ENVIRONMENTAL EXPOSURES IN A GENETICALLY PREDISPOSED INDIVIDUAL, USUALLY OVER 60 YEARS OF AGE, LEADS TO PHENOTYPIC AND FUNCTIONAL ALTERATIONS OF THE LUNG EPITHELIUM. ABERRANT ACTIVATION OF EPITHELIAL CELLS RESULTS, THROUGH A COMPLEX RELEASE OF NUMEROUS MEDIATORS, IN THE LOCAL EXPANSION OF PECULIAR SUBSETS OF AGGRESSIVE FIBROBLASTS AND MYOFIBROBLASTS, WHICH ARE CRUCIAL EFFECTOR CELLS OF FIBROTIC REMODELING AND LOSS OF THE NORMAL LUNG ARCHITECTURE AND FUNCTION. PROGRESSIVE INCREASE OF THE MECHANICAL STIFFNESS ACTIVATES CELL-AUTONOMOUS AND MATRIX-DEPENDENT PROCESSES CONTRIBUTING TO THE PERPETUATION OF THE FIBROTIC RESPONSE. THIS PERSPECTIVE PROVIDES AN INTEGRAL OVERVIEW OF THE MAJOR RISK FACTORS UNDERPINNING THE PATHOGENESIS OF IPF, INCLUDING GENE VARIANTS, AGING ALTERATIONS, ENVIRONMENTAL FACTORS, HOST RISK FACTORS, AND EPIGENETIC REPROGRAMMING. 2021 19 5325 34 PULMONARY PATHOGEN-INDUCED EPIGENETIC MODIFICATIONS. EPIGENETICS GENERALLY INVOLVES GENETIC CONTROL BY FACTORS OTHER THAN OUR OWN DNA SEQUENCE. RECENT RESEARCH HAS FOCUSED ON DELINEATING THE MECHANISMS OF TWO MAJOR EPIGENETIC PHENOMENA: DNA METHYLATION AND HISTONE MODIFICATION. AS EPIGENETICS INVOLVES MANY CELLULAR PROCESSES, IT IS NO SURPRISE THAT IT CAN ALSO INFLUENCE DISEASE-ASSOCIATED GENE EXPRESSION. A DIRECT LINK BETWEEN RESPIRATORY INFECTIONS, HOST CELL EPIGENETIC REGULATIONS, AND CHRONIC LUNG DISEASES IS STILL UNKNOWN. RECENT STUDIES HAVE REVEALED BACTERIUM- OR VIRUS-INDUCED EPIGENETIC CHANGES IN THE HOST CELLS. IN THIS REVIEW, WE FOCUSED ON RESPIRATORY PATHOGENS (VIRUSES, BACTERIA, AND FUNGI) INDUCED EPIGENETIC MODULATIONS (DNA METHYLATION AND HISTONE MODIFICATION) THAT MAY CONTRIBUTE TO LUNG DISEASE PATHOPHYSIOLOGY BY PROMOTING HOST DEFENSE OR ALLOWING PATHOGEN PERSISTENCE. 2023 20 2162 45 EPIGENETIC MECHANISMS IN COPD: IMPLICATIONS FOR PATHOGENESIS AND DRUG DISCOVERY. INTRODUCTION: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS THE FOURTH LEADING CAUSE OF DEATH WORLDWIDE. THE GROWING BURDEN OF COPD IS DUE TO CONTINUOUS TOBACCO USE, WHICH IS THE MOST IMPORTANT RISK FACTOR OF THE DISEASE, INDOOR FUMES, OCCUPATIONAL EXPOSURES AND ALSO AGING OF THE WORLD'S POPULATION. EPIGENETIC MECHANISMS SIGNIFICANTLY CONTRIBUTE TO COPD PATHOPHYSIOLOGY. AREAS COVERED: THIS REVIEW FOCUSES ON DISEASE-RELEVANT CHANGES IN DNA MODIFICATION, HISTONE MODIFICATION AND NON-CODING RNA EXPRESSION IN COPD, AND PROVIDES INSIGHT INTO NOVEL THERAPEUTIC APPROACHES MODULATING EPIGENETIC MECHANISMS. RECENT FINDINGS REVEALED, AMONG OTHERS, GLOBALLY CHANGED DNA METHYLATION PATTERNS, DECREASED LEVELS OF HISTONE DEACETYLASES AND REDUCED MICRORNAS LEVELS IN COPD. THE AUTHORS ALSO DISCUSS A POTENTIAL ROLE OF THE CHROMATIN SILENCING POLYCOMB GROUP OF PROTEINS IN COPD. EXPERT OPINION: COPD IS A HIGHLY COMPLEX DISEASE AND THERAPY DEVELOPMENT IS COMPLICATED BY THE FACT THAT MANY SMOKERS DEVELOP BOTH COPD AND LUNG CANCER. OF INTEREST, COMBINATION THERAPIES INVOLVING DNA METHYLTRANSFERASE INHIBITORS AND ANTI-INFLAMMATORY DRUGS PROVIDE A PROMISING APPROACH, AS THEY MIGHT BE THERAPEUTIC FOR BOTH COPD AND CANCER. ALTHOUGH THE FIELD OF EPIGENETIC RESEARCH HAS VIRTUALLY EXPLODED OVER THE LAST 10 YEARS, PARTICULAR EFFORTS ARE REQUIRED TO ENHANCE OUR KNOWLEDGE OF THE COPD EPIGENOME IN ORDER TO SUCCESSFULLY ESTABLISH EPIGENETIC-BASED THERAPIES FOR THIS WIDESPREAD DISEASE. 2014